Ever since A. J. de Bold et al., Life Sciences, 28, 89 (19-81) reported that an injection of a crude extract of rat atrial myocardium produced an immediate and potent diuretic response in the rat, a great deal of attention has been given to the elucidation of the active principle responsible for this effect, and to understanding the role of the active principle in nature's regulation of body fluid volume and blood pressure. For a review of these developments, see M. Cantin and J. Genest, Endocrine Reviews, 6, 107 (1985). As a result, the active principle in the rat atrium has been shown to be derived from a prohormone containing 152 amino acids. In human atrium, a corresponding prohormone containing 151 amino acids has been identified. Subsequent investigations have established that fragments of the prohormones containing from about 20 to 33 amino acids are more potent than the prohormones themselves, provided that the fragments still contain the C-terminus portion and the cyclic structure of the prohormone. The cyclic structure results from an intramolecular disulfide bridge formed between two half cystine residues at positions 105 and 121 of the peptide sequence. An example of such fragment of the rat prohormone is rANP(101-126) which has the following structure: ##STR1##
The corresponding fragment of the human prohormone, hANP-(101-126), has the same structure except for the replacement of the isoleucyl residue at 110 by a methionyl residue.
Chemists now have synthesized the smaller, more active atrial peptides (i.e. fragments) thus making them readily available for extensive biological investigations and for possible development as diuretic and antihypertensive agents. However, the development of the natural peptides is hampered by their rapid decomposition in vivo by enzymatic processes. Accordingly several investigators are now looking at derivatives or analogs of the natural atrial peptides as a source for potential drugs with improved stability, potency and duration of action over the natural peptides. For example, see L. Johnson et al., PCT patent application WO85/04870, published Nov. 7, 1985; J. Rivier and F. Edouard, PCT patent application WO85/04872, published Nov. 7, 1985; S. Sakakibara, European patent application 85306085.3, published Mar. 5, 1986; and J. D. Mogannam et al. Abstracts of the First World Congress on Biologically Active Atrial Peptides, American Society of Hypertension, May 31-June 1, 1986, New York, N.Y. p. 108A, Japanese patent application 61161299, published July 21, 1986; Japanese patent application 61233698, published Oct. 17, 1986; and Japanese patent application 61243100. published Oct. 29, 1986.
The present application discloses new atrial peptide derivatives having a favorable biological profile which renders them useful as diuretic and antihypertensive agents.